Modelling of the 177mLu/177Lu radionuclide generator

In order to determine the potential of 177mLu/177Lu radionuclide generator in 177Lu production it is important to establish the technical needs that can lead to a clinically acceptable 177Lu product quality. In this work, a model that includes all the processes and the parameters affecting the performance of the 177mLu/177Lu radionuclide generator has been developed. The model has been based on the use of a ligand to complex 177mLu ions, followed by the separation of the freed 177Lu ions. The dissociation kinetics of the Lu-ligand complex has been found to be the most crucial aspect governing the specific activity and 177mLu content of the produced 177Lu. The dissociation rate constants lower than 1*10-11 s-1 would be required to lead to onsite 177Lu production with specific activity close to theoretical maximum of 4.1 TBq 177Lu/mg Lu and with 177mLu content of less than 0.01%. Lastly, the calculations suggest that more than one patient dose per week can be supplied for a period of up to 7 months on starting with the 177mLu produced using 3 g Lu2O3 target with 60% 176Lu enrichment. The requirements of the starting 177mLu activity production needs to be adapted depending on the required patient doses, and the technical specifications of the involved 177mLu-177Lu separation process.


Introduction
Lutetium-177 is a βand γ ray emitting radionuclide with a half-life (t 1/2 ) of 6.64 days and with proven potential in the field of nuclear medicine (Banerjee et al., 2015;Volkert et al., 1991). The 177 Lu labelled [ 177 Lu]Lu-DOTATATE has been FDA approved for neuroendocrine tumour treatment. Other 177 Lu labelled compounds have shown promising application in the treatment of a wide range of tumours, such as prostate cancer, breast cancer, etc. (<transition metals into a; Hofman et al., 2018;Rasaneh et al., 2010;Repetto-Llamazares et al., 2018;Blakkisrud et al., 2017). It is believed that the tremendous potential of 177 Lu is not fully exploited yet and the application of 177 Lu in the treatment of tumours is expected to grow significantly in the coming years (Banerjee et al., 2015;Das and Banerjee, 2016;Vallabhajosula et al., 2001). The present worldwide 177 Lu supply is fulfilled by the direct and the indirect production routes (shown in Fig. 1 in red and blue respectively). The direct route involves the production of 177 Lu by the neutron capture of 176 Lu enriched Lu 2 O 3 targets, while the indirect approach is based on the neutron irradiation of 176 Yb enriched Yb 2 O 3 targets. Recently, an alternative 177 Lu production route via a 177m Lu/ 177 Lu radionuclide generator has been proposed (shown in Fig. 1 in green) (De Vries and Wolterbeek, 2012). The 177m Lu/ 177 Lu radionuclide generator is based on the 177 Lu production from the decay of its long-lived nuclear isomer, 177m Lu (t 1/2 = 160.44 days), and concerns the separation of two isomers in the form of complexed 177m Lu and freed 177 Lu ions (Bhardwaj et al., 2017(Bhardwaj et al., , 2019. Like other radionuclide generators (Roesch and Riss, 2010;Pillai et al., 2012;Roesch, 2012;Knapp et al., 2016;Boyd, 1982;Knapp and Mirzadeh, 1994;Dash and Chakravarty, 2014), the 177m Lu/ 177 Lu radionuclide generator also offers unique advantages like an onsite and on demand 177 Lu supply. However, the development of 177m Lu/ 177 Lu radionuclide generator is still at an early stage.
There are several uncertainties regarding the technical needs of a 177m Lu/ 177 Lu radionuclide generator and what 177 Lu quality (specific activity and 177m Lu content) & quantity (number of patient doses) can be delivered by the generator. It is unclear how much starting 177m Lu activity would be needed to produce sufficient amounts of 177 Lu via a 177m Lu/ 177 Lu radionuclide generator route. The existing literature shows that the dissociation kinetics of the complex used to hold 177m Lu ions is of paramount importance in determining the quality of produced 177 Lu (Bhardwaj et al., 2017(Bhardwaj et al., , 2019. However, what dissociation rate constants are required to lead to clinically acceptable 177 Lu production is not known. In the present work, the existing knowledge regarding the 177m Lu production and the 177m Lu-177 Lu separation have been evaluated together in order to define the technical needs of a 177m Lu/ 177 Lu radionuclide generator. Here, the processes and the parameters affecting the development of a 177m Lu/ 177 Lu radionuclide generator have been simulated. The effect of starting 176 Lu enrichment, the starting 177m Lu activity (and specific activity) and the 177m Lu-177 Lu separation on the quality, quantity of produced 177 Lu have been defined. Finally, the expected 177 Lu quality (its specific activity & 177m Lu content) achievable via a 177m Lu/ 177 Lu radionuclide generator has been compared with the 177 Lu produced by the commercially employed direct and indirect production routes.

Model description
The existing literature shows that the 177m Lu/ 177 Lu radionuclide generator based 177 Lu production consists of three processes (i) the production of 177m Lu (ii) the complexation of the produced 177m Lu ions with a ligand and the 177 Lu production by the separation of complexed 177m Lu and freed 177 Lu ions (Bhardwaj et al., 2019(Bhardwaj et al., , 2020. The parameters affecting these individual processes are shown in Fig. 2. The effect of these parameters has been simulated to determine the 177 Lu activity (number of patient doses) and the quality (its specific activity and 177m Lu content) that can be produced from a 177m Lu/ 177 Lu radionuclide generator.
The 177m Lu/ 177 Lu radionuclide generator based 177 Lu production starts with the 177m Lu production. The 177m Lu production by the neutron irradiation of 176 Lu enriched Lu 2 O 3 target has been shown to be affected by neutron flux, the starting 176 Lu enrichment and the irradiation time (Bhardwaj et al., 2020). At the end of the 177m Lu production, the 177m Lu containing target needs to be dissolved and complexed with a ligand. Uncomplexed 177 Lu that can be eluted from generator is produced by the internal conversion decay of 177m Lu according to Equation (1), (1)

Fig. 2.
A schematic representation of the steps involved in 177 Lu production via a 177m Lu/ 177 Lu radionuclide generator, the ( ) represents the input/output parameters, while the ( ) represents a process.
where A 0 177mLu is the initial activity of 177m Lu at time, t = 0, before 177 Lu separation, λ g , λ m are decay constants of 177 Lu, 177m Lu respectively, A t 177Lu is the activity of 177 Lu produced by internal conversion at time t, B.R is the branching ratio for 177m Lu to 177 Lu decay (21.4%) (Kondev, 2003) and P.I.C is the probability of internal conversion (96.8%) (Bhardwaj et al., 2017).
The accumulation period (the period between two successive 177 Lu separations) and the starting 177m Lu activity determines the maximum 177 Lu activity that can be produced from a 177m Lu/ 177 Lu radionuclide generator. After the accumulation period, a separation process is needed to separate the freed 177 Lu from complexed 177m Lu ions. The efficiency of this separation process determines the number of patient doses that can be provided from the 177m Lu/ 177 Lu radionuclide generator. Further, the specific activity of the starting 177m Lu is one of the crucial parameters in determining the amount of other Lu ions that gets complexed during the 177m Lu complexation. The dissociation of the complex can release the complexed ions free, thereby making them inseparable from the 177 Lu ions freed by the internal conversion decay. This increases the 177m Lu content and decreases the specific activity of the produced 177 Lu, in accordance with Equation (2) below: In every separation step all the dissociated lutetium is extracted and only complexed lutetium is left in the generator for the accumulation period. During the separation process, certain amount of lutetium may become free due to dissociation, and those free lutetium ions could associate again with free ligand. However, the low concentration of free ligand and free lutetium during the separation process make the rate of re-association much slower that the dissociation and for the shake of ease the association term is neglected from the calculations. The dissociation of the complex has been assumed to follow a first order dissociation kinetics according to Equation (3) and (4) below: where, [LuLig] 0 is the initial concentration of the complexed Lu ions and [LuLig] t represents the concentration of complexed Lu ions at time t. k d is the dissociation rate constant in s -1 and t is the separation time taken to separate the complexed and free ions. The dissociation is majorly governed by the dissociation rate constant (k d ) which is dependent on the temperature (T), as per the Arrhenius equation, (k d = A.exp(-E a /RT), where T is the temperature) and time t. A decrease in temperature (T) or reducing the time (t) taken to achieve the separation can decrease the dissociation of starting complex. The effect of dissociation kinetics has been minimized by considering the temperature during the 177 Lu accumulation period to be 77 K. It has been assumed that the dissociation of the complex can only take place during the time taken to separate the freed 177 Lu and the complexed 177m Lu. This assumption is based on an experimental design proposed previously by Bhardwaj et al. (2019).

Methods
The 177m Lu production was simulated using the previously proposed model and MATLAB program (Bhardwaj et al., 2020). The 177m Lu activity produced was used as an input and Equations (1)-(4) were used to simulate the 177 Lu production. Amongst all the parameters shown in Fig. 2, some were kept constant during the simulations with their values listed in Table 1, while the other parameters are discussed below:

Effect of 176 Lu enrichment on 177m Lu production
The effect of the target 176 Lu enrichment (ranging from 2.56%, 40%, 60%, 80%, 99.99%) on the produced 177m Lu activity and specific activity was studied. The four different neutron flux values and the irradiation conditions used in the calculations are listed in Table 1.

Effect of starting 177m Lu activity on number of patient doses
The number of patient doses were determined as a function of time for different starting 177m Lu activity produced from different 176 Lu enrichment (ranging from 60%, 99.99% 176 Lu) containing Lu 2 O 3 target. It was assumed that 177 Lu would be separated after accumulation period of 7 days and the 177 Lu produced can be collected with a 100% separation efficiency, as mentioned in Table 1.

Effect of dissociation kinetics of the Lu-Ligand on 177m Lu-177 Lu separation
A starting 177m Lu activity of 0.08 TBq with a specific activity of 0.33 TBq g -1 Lu produced from 1 g with an 84.44% 176 Lu enriched Lu 2 O 3 target was used as an input for 177m Lu complexation with a ligand (Bhardwaj et al., 2020). The effect of dissociation kinetics on the 177m Lu content and the specific activity of the produced 177 Lu was considered only during the separation of complexed 177m Lu and freed 177 Lu ions. The dissociation rate constants (ranging from 6.25*10 -12 s -1 -1.0*10 -10 s -1 ) for different 177m Lu-177 Lu separation times (1 min, 5 min & 10 min) were used in the calculation, while keeping the 177 Lu accumulation period fixed to 7 days. The effect of dissociation rate constants was also studied at different 177 Lu accumulation period of 7, 14, and 21 days for a fixed 177m Lu-177 Lu separation time of 10 min.

Effect of starting 177m Lu specific activity on the 177 Lu production
The specific activity of 177 Lu produced in the studied dissociation rate constant range, 6.25*10 -12 s -1 -1.0*10 -10 s -1 was evaluated as a function of the starting 177m Lu specific activity (or starting 176 Lu enrichment used in 177m Lu production) for fixed 177m Lu-177 Lu separation time of 10 min, 1 min and 177 Lu accumulation period of 7 days.

Results and discussion
The section begins with evaluating the influence of 176 Lu enrichment on the 177m Lu production. Subsequently, the effect of starting 177m Lu activity, specific activity (or starting 176 Lu enrichment) on the produced 177 Lu activity and specific activity have been defined for different dissociation rate constants and the 177m Lu-177 Lu separation time.

Table 1
List of the values ascribed to different parameters used during the modelling of processes involved in 177m Lu/ 177 Lu radionuclide generator.

Effect of 176 Lu enrichment on 177m Lu production
The availability of sufficient 177m Lu activity is an important requirement for the 177m Lu/ 177 Lu radionuclide generator. The 177m Lu production has been based on the irradiation of 176 Lu enriched Lu 2 O 3 targets in nuclear reactor. Fig. 3 shows the effect of different 176 Lu target enrichment on the maximum 177m Lu activity, specific activity produced under the irradiation conditions listed in Table 1.
It can be seen from Fig. 3 that the increase in the 176 Lu target enrichment leads to an increase in both the activity and specific activity of 177m Lu produced. The 177m Lu activity increases proportionally with the increase in the starting 176 Lu enrichment (Bhardwaj et al., 2020). However, the increase in the 177m Lu specific activity does not follow a proportional behaviour and increases rapidly with an increase in the 176 Lu enrichment. A maximum 177m Lu activity of 0.09 TBq, with a specific activity of 0.65 TBq 177m Lu/g Lu can be produced using 1 g of 99.99% 176 Lu enriched Lu 2 O 3 target. The decrease in the 176 Lu enrichment from to 99.99%-84.44% leads to about a half of the specific activity of the produced 177m Lu. The initial 176 Lu enrichment used in the 177m Lu production is crucial in evaluating the overall cost and the feasibility of the radionuclide generator based 177 Lu production. In addition, the starting 177m Lu activity and specific activity are important in determining the activity, 177m Lu content and the specific activity of produced 177 Lu.

Effect of starting 177m Lu activity (or 176 Lu enrichment) on the number of patient doses
The number of patient doses that can be delivered from a 177m Lu/ 177 Lu radionuclide generator is an important practical aspect that should be considered before evaluating the possibility of its commercialization. Fig. 4 displays the number of patient doses that can be obtained from the 177m Lu produced using 1 g of different 176 Lu enriched targets.
It can be seen from Fig. 4 that the number of patient doses that can be produced from a 177m Lu/ 177 Lu radionuclide generator decreases on decreasing the 176 Lu enrichment used in 177m Lu production. This is expected as the amount of patient doses will be determined by the 177 Lu activity produced which is directly proportional to the starting 177m Lu activity (or the starting 176 Lu enrichment), in accordance with Equation (1). The use of 99.99% 176 Lu enriched target can provide up to 1 patient dose weekly in the first 90 days and decreases to less than one patient dose weekly with the further increase in time. The use of 60% 176 Lu enriched Lu 2 O 3 target would provide less than 1 patient dose weekly during the life of generator. Thus, the irradiation of larger masses of starting Lu 2 O 3 target would be needed in order to reach more than one patient dose. For instance, the use of 3 g 60% Lu 2 O 3 target will result in more than one patient dose per week for a period of up to 7 months. A further decrease in the starting 176 Lu enrichment would increase the target mass needed to produce one patient dose per week for a long period of time. To the best of our knowledge, the 176 Lu enriched Lu 2 O 3 (60%-84.44%) is commercially available in the order of few milligrams Fig. 3. The maximum 177m Lu activity produced (solid line and y axis, on the left) and its specific activity (dashed lines and y axis, on the right) as a function of 176 Lu enrichment in the starting Lu 2 O 3 target. The time of irradiation used for the calculations (t irradiation ) is 4, 6, 11, 40 days (corresponding to maximum activities produced for each case) for the thermal neutron flux of 2.5*10 15 , 1.5*10 15 , 8*10 14 and 2*10 14 cm -2 s -1 respectively and the cooling time is t cooling = 60 days. Fig. 4. The total number of patient doses that can be produced weekly from the 177m Lu produced using 1 g of different 176 Lu enrichment containing targets. and its availability in the order of grams should be investigated in future research.
Further it should be noted that the current direct route 177 Lu production uses 1-5 mg of enriched target to provide about 100 patient doses while the indirect route can lead to about 50 patient doses using 100 mg of the target (depending on the target enrichment and the neutron flux) (De Vries and Wolterbeek, 2012;Lebedev et al., 2000;Dash et al., 2015). The irradiation has to be performed every week and the produced patient doses ( 177 Lu) should be used preferably within one week owing to its half-life of 6.64 days. In the case of 177m Lu/ 177 Lu radionuclide generator, the irradiation would be needed once in 6-7 months and the 177 Lu could be produced when needed.
Lastly, it should also be mentioned that the number of patient doses (or produced 177 Lu activity) will also get effected by the efficiency of the separation process responsible for obtaining the freed 177 Lu ions. The separation efficiency will depend on the chemical design of a radionuclide generator system and it can be expected to vary from 60% to 99% on the basis of the available literature (Bhardwaj et al., 2017(Bhardwaj et al., , 2019. Moreover, with an increasing number of separations and storage, the elution efficiency may drop further for chemical, physicochemical or radiolytic reasons and should be evaluated in future research. , A max = 0.08 TBq, S.A = 0.33 TBq/g Lu, t irr = 11 days, t cooling = 60 days). The shaded regions on the yaxis (left) represents the 177 Lu/ 177m Lu activity ratios that can be achieved commercially and the y-axis is the theoretical maximum specific activity of 4.1 TBq/ mg Lu (Wright et al., 1996).

Effect of the dissociation kinetics on the 177m Lu content and specific activity of the produced 177 Lu
The specific activity of the 177 Lu produced and its 177 Lu/ 177m Lu activity ratio is largely dependent on the dissociation of the complexed Lu. The effect of dissociation rate constant on the specific activity of the produced 177 Lu and the accompanying 177 Lu/ 177m Lu activity ratio for different 177m Lu-177 Lu separation time is shown in Fig. 5(a) and for different 177 Lu accumulation period is shown in Fig. 5(b). Fig. 5(a) shows that the decrease in the 177m Lu-177 Lu separation time leads to a proportional increase in the 177 Lu/ 177m Lu activity ratio while the specific activity remains close to the theoretical maximum of 4.1 TBq 177 Lu/mg Lu. A 177m Lu-177 Lu separation time of 1 min would provide with an ideal separation leading to 177m Lu content of less than 0.01% for the studied dissociation rate constants (i.e. ranging from 6.25*10 -12 -1*10 -10 s -1 ). A 177m Lu-177 Lu separation time of 10 min will result in a 10 times decrease in the 177 Lu/ 177m Lu activity ratio making the use of dissociation rate constants higher than 2.5*10 -11 s -1 clinically unacceptable. It should be noted that the 177m Lu-177 Lu separation time of 10 min has already been experimentally achieved in the existing literature (Bhardwaj et al., 2019). Further, the existing technologies such as microfluidics (Ciceri et al., 2014), capillary electrophoresis (Zhu and Lever, 2002) are few attractive options that can allow reaching 177m Lu-177 Lu separation time up to 1 min. However, their potential in 177 Lu-177m Lu separation has not been experimentally proved yet and should be evaluated in future investigations. Fig. 5(b) shows that an increase in the 177 Lu accumulation period increases the 177 Lu/ 177m Lu activity ratio while keeping the 177 Lu specific activity in the range of 2.9-4.1 TBq 177 Lu/mg Lu. The use of a ligand with a dissociation rate constant ranging from 1.25*10 -11 -5*10 -11 s -1 would result in the 177 Lu/ 177m Lu activity ratios ranging from 3000 to 10000, depending on the 177 Lu accumulation period. Accumulation period of about 15-30 days would be needed to get the 177 Lu/ 177m Lu activity ratio higher than 3000. This is expected as the 177 Lu activity increases with the increase in 177 Lu accumulation period (in accordance with Equation (1)). The 54% of the maximum 177 Lu activity grows after about 7 days of accumulation period, increasing from 75% to 88% after 14 days and 21 days of accumulation, respectively. The use of complexes with dissociation rate constants lower than 1.25*10 -11 s -1 , will keep the 177m Lu content less than 0.01% and 177 Lu specific activity close to theoretical maximum of 4.1TBq 177 Lu/mg Lu irrespective of used 177 Lu accumulation period.
Overall, the achievable 177 Lu quality is better than the one produced by the current direct and indirect production route. The indirect 177 Lu production has been reported to result in 177 Lu specific activity ranging from 2.9 TBq/mg Lu to theoretical maximum of 4.1 TBq/mg Lu with 177m Lu content less than 0.01% 177m Lu (the 177 Lu/ 177m Lu activity ratio ≥ 10,000) (Valery et al., 2015;Knapp et al., 2004;Ponsard, 2007;Ketring et al., 2003;Zhu and Lever, 2002;<Production and chemical). The reported specific activity values produced via the direct route production ranges from 500 GBq/mg Lu -2.8 TBq/mg Lu depending on the starting target enrichment and the neutron flux (Valery et al., 2015;Knapp et al., 1996Knapp et al., , 2005Ponsard, 2007;Ketring et al., 2003;Mikolajczak et al., 2003). Further, the direct production has been reported to lead to the 177 Lu/ 177m Lu activity ratios ranging from 4000-10,000 (at the EOI) depending on the used irradiation time, neutron flux and the target enrichment (Dvorakova et al., 2008;Pawlak et al., 2004;Knapp et al., 1995;Das et al., 2007;Chakraborty et al., 2014). It should be pointed out that the reported values have been based at the end of irradiation. However, the hospitals use 177 Lu up to one week after the end of irradiation and during this time the 177 Lu/ 177m Lu activity ratio is likely to be halved (Banerjee et al., 2015).

Effect of starting 177m Lu specific activity on the specific activity of produced 177 Lu
Apart from the dissociation rate constant, the specific activity of the produced 177 Lu also gets affected by the specific activity of the starting 177m Lu which is related to the initial 176 Lu enrichment (as shown previously in Fig. 3). Fig. 6 presents the 177 Lu specific activity that can be produced when starting with 1 g of different 176 Lu enrichment containing targets and dissociation rate constants ranging from 6.25*10 -12 s -1 -1*10 -10 s -1 . Fig. 6(a), (b) have been based on a 177m Lu-177 Lu separation time of 10 min and 1 min respectively. Fig. 6(a) and (b) clearly highlights the important role of the 177m Lu-177 Lu separation time in determining the specific activity of 177 Lu produced. The use of a 177m Lu-177 Lu separation time of 1 min will keep the 177 Lu specific activity close to the theoretically maximum of 4.1 TBq/mg Lu irrespective of the starting 176 Lu enrichment ( Fig. 6(b)) while it gets affected on using a 177m Lu-177 Lu separation time of 10 min.
The decrease in the starting 176 Lu enrichment would decrease the specific activity of the produced 177m Lu (see Fig. 3). The use of low starting specific activity 177m Lu results in high Lu ( 177m Lu, 176 Lu, 175 Lu) ion contribution due to dissociation, thereby lowering the specific activity of produced 177 Lu ions. The use of complex with a dissociation rate constant of an order of 1.25*10 -11 s -1 can lead to specific activity close to 4.1 TBq/mg Lu irrespective of the initial 176 Lu enrichment and 177m Lu-177 Lu separation time. However, the use of a complex with dissociation rate constants higher than 5*10 -11 s -1 results in a considerable difference in the specific activity of the produced 177 Lu, ranging from 3.9 TBq/mg Lu to 1.12 TBq/mg Lu, depending on the starting 176 Lu enrichment and 177m Lu-177 Lu separation time. It should be noted that the lowest specific activity of 1.12 TBq/mg Lu produced on starting with 1 g 40% 176 Lu enrichment containing target is very well comparable to the 177 Lu produced during the direct route.
Overall, the results from Figs. 5 and 6 indicate that the dissociation rate constants higher than 1*10 -10 s -1 are unacceptable irrespectively of the employed 177 Lu accumulation period or 177m Lu-177 Lu separation time (1 min-10 min) as they lead to high 177m Lu content in the produced 177 Lu. The dissociation rate constant of the order of 10 -7 s -1 (at pH-5, 20 • C) has been reported in the literature for the chemically similar Y-DOTA complex (Jurkin et al., 2007) and dissociation rate constants of the order of 10 -8 s -1 have been reported for Lu-DOTATATE complex (at pH-4.3, and 20 • C) (van der Meer et al., 2013). The contribution from the complex dissociation can be further decreased by lowering the temperature in which the accumulation and separation take places (as per the Arrhenius equation (k d = A.exp(-E a /RT), where T is the temperature) and by shortening the time required to carried out the 177 Lu extraction. This concept was applied successfully in our previous publication and a dissociation rate constant of 5*10 -8 ±1.3*10 -8 s -1 was calculated for a Lu-DOTA complex while the 177 Lu accumulation period occurred at a temperature of 77 K and the 177m Lu-177 Lu separation process lasted for 10 min (Bhardwaj et al., 2019).

Conclusions
The presented work establishes the technical needs and potential of the 177m Lu/ 177 Lu radionuclide generator in the 177 Lu production. The effect of 176 Lu enrichment and the 177m Lu-177 Lu separation conditions on 177 Lu production have been studied. Depending on the starting 176 Lu enrichment, large target masses might be required to produce sufficient 177 Lu. For instance, the irradiation of 3 g, 60% 176 Lu enriched Lu 2 O 3 target would be needed to produce more than one patient dose per week for a period of up to 7 months. Further, the use of initial 176 Lu enrichment varying from 40% to 99.99% could lead to 177 Lu specific activity ranging from 1.2 to 3.9 TBq 177 Lu/mg Lu, depending on the used 177m Lu-177 Lu separation conditions. The dissociation rate constants involved during the 177m Lu-177 Lu separation would be crucial in governing the specific activity and 177m Lu content of produced 177 Lu. The dissociation rate constants ≤1*10 -11 s -1 would be needed to produce 177 Lu with less than 0.01% of the 177m Lu content and with specific activity close to a theoretical maximum of 4.1 TBq 177 Lu/mg Lu.
Finally, it should be noted that this work has been based on the use of a ligand for complexing Lu ions post 177m Lu production and provides a reflection on the order of kinetic stability needed for the immobilization of Lu ions. The method for Lu ion immobilization can very well be varied while keeping in mind the needed kinetic stability.

Declaration of competing interestCOI
All authors have participated in (a) conception and design, or analysis and interpretation of the data; (b) drafting the article or revising it critically for important intellectual content; and (c) approval of the final version.